Quaternary ammonium salts of chrysanthemum acids



thirteen,

United 3,261,838 QUATERNARY AMMONIUM SALTS F CHRYSANTHEMUM ACIDSReginald L. Wakeman, Philadelphia, Pa., and Edward Griftin Shay, BelleMead, N.J., assignors, by mesne assignments, to Milimaster OnyxCorporation, New York, N.Y., a corporation of New York No Drawing. FiledApr. 23, 1964, Ser. No. 362,558 4 Claims. (Cl. 260-286) The object ofthe present invention is the preparation of relatively water-insoluble,microbiologically active compounds by reaction of certain quaternaryammonium hydroxides or their salts with chrysanthemum acids.

The products of this invention conform, in general, to the followingstructure:

wherein X may be a methyl group or a COOZ' group, and Z and Z arecations of microbiologically active quaternary ammonium compounds.

The chrysanthemum acids include chrysanthemum-- monocarboxylic acid andchrysanthemumdicarboxylic acid which are, respectively,2,2-dimethyl-3-(2-mthylpropenyl) propanecarboxylic acid and3-carboxy-alpha-2,2- trimethyl cyclopropaneacrylic acid; they arecomponents of pyrethrum and are also manufactured synthetically and arecommercially available.

Typical examples of the quaternary ammonium compounds which may be usedin this invention are the alkyl trimethyl ammonium chlorides,alkyl-benzyl trimethyl ammonium chlorides, alkyl dimethyl benzylammonium chlorides, alkyl dimethyl menaphthyl ammonuim chlorides, alkyldimethyl substituted-benzyl ammonium chlorides in which the benzylradical is substituted with one or more side chains containing from 1 to5 carbon atoms such, for example, as methyl, di-methyl, ethyl and thelike and in which the carbon atoms may all be in the same or differentside chains or in which the benzyl radical bears one, two or morehalogen atoms such as chlorine or bromine, alkyl pyridinium chlorides,alkyl isoquinolinium chlorides and bromides, alkyl lower-alkylpyrrolidinium chlorides, alkyl lower-alkyl monpholiniu-m chlorides inall of which the alkyl group may have from 8 to 22 carbon atoms and thelower-alkyl 'group may have from 1 to 4 carbon atoms and alkyl phenoxyethoxy ethyl dimethyl benzyl ammonium chloride in which the alkylradical may also be iso-octyl or nonyl and in which the phenyl radicalmay, if desired, be substituted by a methyl radical. Various otheranalogs of these quaternanies may also be employed such, for example, ascetyl dimethyl ethyl ammonium bromide or oleyl dimethyl ethyl ammoniumbromide.

In general, the quaternary ammonium compounds use- :ful in thisinvention are the higher alkyl quaternary ammonium hydroxides, halides(chlorides and bromides), sulfates, methosulfates and the likepossessing the following formula:

RI I RIII where R is an alkyl or alkaralkyl radical containing from 8 to22 carbon atoms or an alkyl .phenoxy ethoxy ethyl radical in which R isan alkyl radical containing from 8 to 9 carbon atoms and in which thephenyl radical may be substituted by a methyl group; R and R" are methylor ethyl radicals or members of a heterocyclic ring sysat-exited July19, 19185 tem such as pyridine, isoquiuoline, pyrrolidine andmorpholine; R' is a methyl radical or a benzyl group or asubstituted-benzyl group such, for example, as a monochlorobenzylradical or a dichlorobenzyl radical or mix ture thereof or a methylbenzyl, dimethyl benzyl, ethyl benzyl, diethyl benzyl, isopropyl benzyl,tertiary butyl benzyl or another benzyl radical containing from 1 to 5carbon atoms as side chains, either as a single side chain or amultiplicity of side chains including mixtures thereof or a menaphthylgroup or hydrogenated menaphthyl group. When R and R" are members of amorpholine or pyrrolidine ring, R' is a methyl, ethyl, propyl or butylgroup. When R and R" are members of an unsaturated heterocyclic ringsuch as pyridine or isoquinoline, R is the same radical as R". X in theabove 'formula corresponds to a halide radical such as chloride, bromideor iodide or to any other water-soluble anion such as methosulfate.

In general, we prefer to use such quaternary ammonium compounds whichhave a phenol coeflicient of at least with respect to bothStaphylocofccus aureus and Salmonella typhosa at 20 C. when determinedby the standard method given in the Official Methods of Analysis of theAssociation of Ofiicial Agricultural Chemists, ninth edition (1960),page 63 et seq.

The compounds of this invention may be prepared by mixing aqueoussolutions of the quaternary ammonium salts or hydroxides with an aqueoussolution of chrysanthemurnmonocarboxylic or chrysanthemumdicarboxylicacid or with any of their water-soluble salts.

After thorough mixing, the organic product layer is separated from theaqueous layer (as with a separatory funnel) since two distinct phasesare formed. Separation may be facilitated by the addition of an organicsolvent immiscible with water. The product layer may be washed withwater to remove any residual by-product salt or unreacted materials. Thesolvent, if any, may be evaporated and the product air or vacuum driedto a paste, wax, oil, or solid.

It is not necessary to use an aqueous medium. Any solvent or solventmixture in which the starting materials are soluble will besatisfactory. Non-aqueous solvents facilitate the separation ofbyproduct inorganic salt and reduce the need for vacuum drying to get ananhydrous product. When a non-aqueous medium is employed, it is usuallynecessary to add a small amount of water to facilitate ionic reaction.

The product may be used, if desired, without drying since any entrappedwater is irrelevant to the microbiological activity of the compounds. Inother applications, removal of water may be essential for reasons notrelated to biological activity.

An alternative method for the preparation of compounds especiallyapplicable to the tpeat nent of fabric, ropes,

r dl -woven, fabr and reticulated 'orconvoluted materials involves atwo-step process'l"lntlie first step, the material is passed through abath containing the anionic moiety. Excess solution is removed bymethods well known to those skilled in the art. The treated material isthen passed through a second bath wherein the concentration ofquaternary ammonium compound is such that the material pickup willresult in an equivalent amount of quaternary ammonium compound reactingwith the anionic moiety, depositing the product in the most intimate wayon the surface and in the interstices, convolutions and reticulations ofthe material.

The method of adjustment of solution concentration to achieve therequired pickup is well known to those skilled in the art. The order oftreatment may be reversed Without affecting the biological activity ordurability of the product on the material. The products of thisinvention may be formulated as water dispersions by disdiillliCH RQ'Giilsolving them in a water miscible organic solvent such as acetone ormethanol and diluting with Water or by dissolving them in emulsifiableoils such, for example, as sulfonated castor oil or pine oil anddiluting with water. In preparing aqueous dispersions, emulsifyingagents such, for example, as ethylene oxide condensates of alkyl phenolsmay be used with or without organic solvents.

It is surprising that the compounds of this invention exhibit highmicrobiological activity despite their relative insolubility in water.Because of their unusual combination of phsyical and microbiologicalproperties, they can be used to impart laundry-resistant anti-microbialcharacteristics to textiles. They can also be used as the active agentin antimildew finishes for textiles which are resistant to leaching withwater.

Although the compounds have low water solubility, they are compatiblewith various organic solvents, plasticizers and high molecular weightcompounds. Consequently, they may be incorporated as anti-microbialagents in synthetic resins and plastics. The compounds are compatiblewith natural and synthetic rubber latices. Therefore, they may be usedto prepare bacteriostatic films and molded objects deposited from suchlatices.

The compounds can be incorporated into cutting and grinding fluidsWithout precipitation. Also, they blend well with non-ionic and anionicsurface active agents. In such compositions they retain theirmicrobiological activity.

It will be understood that the properties of the products describedherein will vary depending upon the nature of the cationic quaternaryammonium compound used in their preparation as well as the anioniccompound reacted therewith.

The chemical, physical and biological properties of the products of ourinvention make them especially appropriate for the followingapplications when suitably incorporated in active amounts in anappropriate vehicle, binder, medium or substrate:

(1) Mildewproofing fabric, canvas, ropes, textiles, awnings, sails,tenting and other woven and non-woven reticulated materials.

(2) Paint rnildewstats.

(3) Jet plane fuel additive to control growth of microorganisms.

(4) Odor preservative agents for clothes and shoes.

(5 Mildew retardant and odor suppressant for shoes and other leatherproducts.

(6) Topical antiseptics.

(7) Antidandruff agents.

(8) Disinfection agents for hair and gut of man and beast.

(9) Bacteriostatic furniture dressing.

(10) Surface finishes for stone, plaster, tile, cement, brick and otherinorganic building materials to retard growth of microorganisms, fungi,mold and algae.

(11) Wool preservative.

(12) Plant and tree spray to combat fungi.

(13) Antimycotic agents for soap wrappers.

(14) Self-sanitizing brushes.

(15) Mildewproofing agent in and on plastic and film.

(16) Mildewproofing of cellulosics, cardboard, fibreboard,

paper and cordage.

(17) Contact biostat for application to film, waxes and cloth topreserve cheese, meats and vegetables and other food products.

(18) Algal inhibition, especially on surfaces and in solution where lowfoaming is desirable.

(19) Paper pulp slime control.

(20) Sanitizing agent for rug, carpet, curtains.

(21) Egg preservation.

(22) Adhesive preservation.

(23) Preservation of latex paints.

(24) Preservation of metal-working compounds.

(25) Additives for soap and for both anionic and nonanionic detergentsin liquid, bar, powder, bead, solution and other forms to impartbacteriostatic and fungistatic properties thereto.

(26) Bacteriostatic agents for household laundry soften- (27) Algastatand bacteriostat in recirculated water for cooling towers, airconditioners and humidifiers.

(28) Bacteriostat and algastat for flood waters and brines used insecondary oil recovery.

(29) Fungistat for seed and soil treatment against damping-otf.

The microbiological activity of our compounds has been evaluated formicrobiological stasis by the Standard Tube Dilution Test, the techniquefor which is common knowledge to those skilled in the art. A Difco BactoCSMA Broth #0826 was used in the study. This test is used to determinethe lowest concentration of microbiologically active compounds whichwill inhibit the growth of the organism in question. For a wide range ofapplications, the inhibition of growth rather than outright kill issatisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of theCSMA Broth in a test tube which is then sterilized in an autoclave. Onecc. solution of the microbiologically active compound at an appropriateconcentration is added to the test tube which is then inoculated with0.1 cc. of a twenty-four hour old culture of the organism under study.The test tube is then incubated at 37 C. for forty-eight hours andobserved for bacterial growth.

The same procedure is followed for fungi. In such tests, however, thetubes are incubated for fourteen days at a temperature suitable foroptimum fungal growth, usually 25 C.

This invention is illustrated by, but not restricted to, the followingexamples:

Example I The potassium salt of chrysanthemummonocarboxylic acid wasobtained by saponifying its ethyl ester with potassium hydroxide. Astock solution of the salt in water was prepared at 40% concentration byweight. An aliquot of this solution containing 0.155 molecular weight ofthe salt was agitated vigorously while adding a chemically equivalentamount of a 10% solution of a commercial grade of alkyl dimethylethyl-benzyl ammonium chloride (Onyx Chemical Corporations ETC-471 inwhich the alkyl distribution is 50% C 30% C 17% C 3% C The mixture wastransferred to a separatory funnel wherein it separated into two phases.The organic product layer was removed and dried in vacuo to yield thealkyl dimethyl ethyl-benzyl ammonium salt of 2,2-dimethyl-3-(2-methylpropenyl)cyclopropanecarboxylic acid as a viscous brown liquidin 98% of the theoretical yield.

Example 11 To an aliquot of the stock solution of potassium salt ofehrysanthemummonocarboxylic acid of Example I was added, while agitatingvigorously, a chemically equivalent amount of a 10% solution of acommercial grade of alkyl dimethyl benzyl ammonium chloride (OnyxChemical Corporations BTC-824 in which the alkyl distribution IS C14,C16, C12, C13). A small amount of benzene was added to facilitate phaseseparation. The organic product layer was separated and dried to yield96% of the theoretical of the alkyl dimethyl benzyl ammonium salt of2,2-dimethyl-3-(2-methylpropenyl) cyclopropanecarboxylic acid as aviscous brown liquid.

Example III In a similar manner, an aliquot of the solution of thechrysanthemummonocarboxylic acid salt was reacted with a chemicallyequivalent amount of an aqueous-alcohol solution of a commercial gradeof alkyl isoquinolinium bromide (Onyx Chemical Corporations Isothan Q-75in which the alkyl distribution is 50% C 30% C 17% C 3% C The reactionmixture was heated to evaporate off the alcohol; a small quantity ofbenzene was added and the mixture transferred to a separatory funnel.The organic product layer was removed and vacuum dried. The product, thealkyl isoquinolinium salt of 2,2-dimethyl-3-(2-methylpropenyl)cyclopropanecarboxylic acid, was recovered in the theoretical yield as adark brown viscous liquid.

Example IV Using the Standard Tube Dilution Test described above, thefollowing bacteriostatic levels were determined. (S.a.=StaphyI0c0ccusaureus, S.t.==Salm0nlella typhosa, A.n.=Aspergillus niger.)

1. A quaternary ammonium compound having the structure:

wherein X is selected from the group consisting of a methyl group and aCOOZ group and Z and Z are cations of a microbiologically activequaternary ammonium compound having a phenol coefficient of at leastwith respect to both Staphylococcus aureus and Salmonella typhosa at 20C. and having at least one alkyl of 8 to 22 carbon atoms on thequaternary nitrogen.

22. The alkyl dimethyl ethyl-benzyl ammonium salt of2,2-dimethyl-3-(Z-methylpropenyl) cyclopropanecarboxylic acid whereinthe alkyl has 8 to 22 carbon atoms.

3. The alkyl dimethyl benzyl ammonium salt of 2,2-dimethyl 3(Z-methylpropenyl) cyclopropanecarboxylic acid wherein the alkyl has 8to 22 carbon atoms.

4. The alkyl isoquinolinium salt of 2,2-dimethyl-3-(2- methylpropenyl)cyclopropanecarboxylic acid wherein the alkyl has 8 to 22 carbon atoms.

References Cited by the Examiner Kastenbaum: The Effect ofChrysanthemummonocarboxylic Acid Upon Respiratory Pathways, DissertationAbstr. 20, 1129 (1959).

Swartz: Surface Active Agents and Detergents, vol. II, Interscience,1958, pages 211, 220 and 222 relied upon.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, NICHOLAS S. RIZZO, Examiners.

D. G. DAUS, Assistant Examiner.

1. A QUATERNARY AMMONIUM COMPOUND HAVING THE STRUCTURE:
 4. THE ALKYLISOQUINOLINUM SALT OF 2,2-DIMETHYL-3-(2METHYLPROPNYL)CYCLOPROPANECARBOXYLIC ACID WHEREIN THE ALKYL HAS 8 TO 22 CARBON ATOMS.